AT7519

Risk prediction models based on multi-omics data and machine learning algorithms provide potential reference targets for prognosis prediction and personalised treatment of cervical cancer patients. The results of this study provide important insights into the understanding of the health risks of cervical cancer associated with Benzo[a]pyrene and Nicotine exposures and the development of preventive and therapeutic strategies for cervical cancer, which may contribute to the development of precision medicine for cervical cancer.

In this study, a potent and selective CDK9 degrader, C3, was developed through PROTAC modification of the CDK9 inhibitor, AT-7519...Our findings indicate that the targeted degradation of CDK9 could become a viable strategy for treating SCLC, highlighting its potential therapeutic value. Additionally, this research offers a general structural optimization and evaluation strategy to improve the degradative selectivity, metabolic stability, and oral availability of PROTAC molecules.

We confirmed the potential importance of cell cycle-mediated regulation of C/EBPδ by showing that four of the most potent C/EBPδ activators-R547, PHA793387, AZD5438 and AT7519, all multi-cyclin-dependent kinase (CDK) inhibitors-limited the clonal expansion of PDAC cells. Next to providing a valuable selection of C/EBPδ-modulating compounds for the use in preclinical studies, this report contributes to our understanding of the molecular regulatory mechanisms of C/EBPδ in general and in PDAC in particular.

After exposure to AT7519 during differentiation, primary human CD4+ T cells presented increased expression of IL17A/F, IFNG and GZMB and decreased expression of PDCD1 and CTLA4. These findings elucidate a previously unrecognized facet of AT7519 activity and suggest the potential incorporation of this molecule into immune therapies to augment the effectiveness of diverse anticancer strategies involving anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) regimens.

In silico molecular docking studies revealed that compounds 4, 7a, 7d, and 9 adopt a similar binding mode as AT7519 (I) within the CDK2 binding site...Based on these findings, it was concluded that the synthesized pyrazole derivatives, particularly compound 4, show potent CDK2 inhibition and significant anticancer activity, with promising drug-like properties and minimal toxicity. This positions them as strong candidates for further development as CDK2-targeting anticancer agents.

In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC.

Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro. A novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9、CAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma.

P1, N=29, Active, not recruiting, National Cancer Institute (NCI)

Subsequently, we suggested that AT-7519 and PHA-793887 might be potential drug agents for high-risk patients. Besides, we explored the potential drug targets and agents for patients with high risk. Our findings offered a fresh idea for personalized prognosis management in HCCs with CTNNB1 mutations and threw new insight for precise treatment in HCCs as well.

Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities.

Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib.

In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties.